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High-Throughput Screening Identifies Ascorbyl Palmitate As a SIRT2 Deacetylase and Defatty-Acylase Inhibitor

Small molecule inhibitors of SIRT2 are being developed because of their therapeutic potential in a variety of diseases. Here, we developed a high-throughput screen to identify novel SIRT2 inhibitors using a fluorescent SIRT2 probe, 1-aminoanthracene (AMA). AMA has high fluorescence when bound to SIRT2, and its fluorescence reduces >10-fold when it is displaced from SIRT2 by other ligands. We used this property of AMA to screen a library of known bioactive compounds for SIRT2 binding and discovered two known pharmaceutical compounds that bind SIRT2 with K d values in the low μM range, ascorbyl palmitate and pictilisib. Both compounds inhibit the deacetylase and defatty-acylase activities of SIRT2. While pictilisib has selectivity for SIRT2, ascorbyl palmitate also inhibits the enzymatic activities of SIRT1 and SIRT6. Finally, we show that ascorbyl palmitate inhibits SIRT2 deacetylase and defatty-acylase activities in cells, and SIRT2 inhibition by ascorbyl palmitate contributes to the cytotoxicity of the compound. Our work discovered novel SIRT2 deacylase inhibitors and presents a screening approach that can be applied on a larger scale.

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S1065 Pictilisib (GDC-0941) Pictilisib (GDC-0941, RG7321) is a potent inhibitor of PI3Kα/δ with IC50 of 3 nM in cell-free assays, with modest selectivity against p110β (11-fold) and p110γ (25-fold). Pictilisib (GDC-0941) induces autophagy and apoptosis. Phase 2.

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Apoptosis related PI3K Autophagy